In this competing renewal application, we will explore the hypothesis that estrogenic compounds may serve as protective agents for the synergistic effects of cocaine/HIV proteins on producing synaptic impairments in the nucleus accumbens, a critical brain region involved in the motor and cognitive dysfunction associated with HIV-1 associated neurocognitive disorder (HAND) and recognized as the main target of the mesotelencephalic dopamine system and the main striatal waystation for circuits of prefrontal origin. The specific aims are: 1) To investigate the role of cocaine/HIV-1 protein-induced synaptic impairment and estrogenic modulation of neuroplasticity. The proposed in vitro experiments will further determine the mechanisms of estrogenic activity and test novel soy isoflavone compounds as potential estrogen -receptor modulators of HIV-protein induced synaptic impairment. 2) To determine the role of estrogen(s) in modulating nucleus accumbens dopaminergic synaptic plasticity following repeated cocaine in chronic HIV-1 protein exposure models. The effects of HIV-1 protein+cocaine on dopaminergic neurochemistry will be assessed using in vivo microdialysis in ovariectomized female HIV-1 transgenic animals. The ability of estrogen/soy isoflavones+ cocaine to produce DAT dysfunction/protection under physiological conditions will be assessed and the behavioral/pathological consequences will be determined. 3) To determine the role of synaptic plasticity in HIV-1 protein+cocaine cognitive behavioral impairments and estrogenic therapeutic effects. Estrogen(s) will be used to modulate cognition and dopamine markers following cocaine and HIV-1, providing insight into potential neuroprotective mechanisms and therapeutic strategies. Investigations will focus on quantifying spine density changes with respect to regulators of nucleus accumbens medium spiny neurons and prefrontal cortical neuronal plasticity. The ultimate goal of this research is to identify sensitive targets and unique pharmacological interventions (estrogen -receptor modulators) for preventing cognitive and motor dysfunction (HAND) following cocaine abuse in HIV-1+ special populations.